The involvement of peroxisome proliferator-activated receptor gamma (PPAR?) in anti-inflammatory activity of N-stearoylethanolamine

Background: N-stearoylethanolamine (NSE) is a bioactive lipid amine with a wide range of biological activities. Anti-inflammatory properties of NSE were previously confirmed on multiple animal models. However, the molecular mechanisms of anti-inflammatory action of NSE remain unclear. In the current study, we examined the involvement of nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR gamma) in the NF-kB -dependent pathway of anti-inflammatory action of NSE using different methodological approaches. Methods: Molecular modeling calculated the possibility of NSE binding PPAR. Ex vivo experiment, using selective agonist of PPAR alpha/gamma - LY-171883 and antagonist of PPAR gamma - GW9662, examined the role of PPAR alpha/gamma in the NSE's effect on nuclear NF-kB translocation in LPS-activated rat peritoneal macrophages. Finally, the NSE's action on mRNA level of PPAR gamma-dependent genes was studied in the liver of insulin-resistant rats. Results: The results of molecular docking showed that NSE could bind to PPAR gamma and compete for the binding site with antagonist GW9662 and agonist LY-171883. These data was supported by in vitro study where pre-treatment with NSE prevented further LPS-induced NF-kB translocation into the nuclei of rat peritoneal macrophages. NSE treatment before GW9662 and LPS addition normalized the level of NF-kB translocation and IL-1 beta content. This finding confirmed a competitive binding of NSE with GW9662 for the ligand-binding domain of PPAR gamma. Additional in vivo study showed that NSE administration changed the mRNA expression of several PPAR gamma target genes, including SLC27A1 encoding fatty acid transport protein-1 and IL1RN - interleukin-1 receptor antagonist in insulin resistant rats. Conclusion: NSE suppressed nuclear translocation of NF-kappa B in LPS-stimulated peritoneal macrophages via PPAR gamma and changed hepatic mRNA expression of PPAR gamma target genes (SLC27A1, IL1RN) in insulin resistant rats.